Head and Neck Squamous Cell Carcinoma (HNSCC), occurs in over 42,000 men and women annually in the United States, resulting in over 13,000 deaths per year. We have, over the last 5 years, initiated a comprehensive investigation of head and neck squamous cell carcinoma. We have an ongoing program with traditional molecular epidemiologic components that is also utilizing emerging molecular pathology techniques to develop a multilevel framework for investigating the etiology, susceptibility, and clinical course of HNSCC. We have successfully identified and approached incident HNSCC cases that occurred in the metropolitan Boston area over the grant period and successfully recruited eligible population-based controls, obtaining biologic specimens from essentially all enrolled participants. We have completed over 10,000 genotypes from DNA extracted from participants and obtained multiple biological samples for future studies. This renewal focuses upon (1) expanding the number and type of candidate genes for study (2) characterization of specific haplotypes and (3) defining the mutagen sensitive phenotype of the newly enrolled subjects and (4) follow-up of enrolled subjects. This will facilitate applying genotype and phenotype characterization in a novel, powerful analytic approach; we will evaluate effect modification including in the model and the well-described interaction of alcohol and tobacco in the genesis of HNSCC. Further, the data will also be applied in ongoing separate studies of the same population addressing somatic gene inactivation and aberrent gene expression on microarray platforms. This renewal will allow for the appropriate, powerful analysis of gene-environment interaction resulting from variants of low penetrant genes in the setting of a multilevel research framework where data can be shared and integrated across scientific investigations. It is being conducted by an outstanding existing team currently in the field. This study seeks to understand any normal genetic variants that control,susceptibility to head and neck cancer associated with smoking and drinking. This proposal work will also act as a foundation for other studies that will dissect these cancers in order to characterize differences in the types of genetic changes in HNSCC.